We study the role in tumorigenesis, of abnormal, promoter, CpG island, DNA hypermethylation and associated epigenetic gene silencing.
Specific Aims 1 and 2 focus on silencing of HIC1 (Hypermethylated in Cancer 1), a gene identified and cloned through this grant support, and for which a mouse knockout model suggests how epigenetic gene silencing may foster cancer initiation. Loss of this transcriptional repressor may allow abnormal cell survival in toxic surroundings common to cancer risk, such as chronic inflammation, thus fostering abnormal clonal expansion.
Aim 3, closely related to the above two, links vulnerability of genes in adult tumorigenesis to acquire abnormal promoter DNA methylation, with key histone modifications, and proteins establishing and interpreting them, in embryonic stem/progenitor cells. This DNA methylation converts a normally plastic transcriptional repression to tight, heritable gene silencing which may facilitate early stem/progenitor clonal expansion.
In Aim1 we pursue our discovery that SIRT1, a deactylase involved in cell stress, cell survival, and gene silencing, complexes with, and is a direct transcriptional repression target of, HIC1. In addition, we linked SIRT1 to the silencing of other DNA hypermethylated cancer genes. We are now exploring a potential feed back loop in which HIC1 mediates its own transcriptional repression through interaction with SIRT1. This step, if it becomes epigenetically heritable, could constitutively increase SIRT1 and foster additional abnormal gene silencing events.
In Aim 2, we use our Hic1 mouse knockout to study whether first steps in cellular transformation may stem from an abnormal epigenetic milieu. In this scenario, cells adopt mechanisms to survive events such as DNA damage by proliferating, and evolving immortalization and/or transformation, rather than apoptosing or senescing. We explore early phenotypic consequences of loss of HIC1, and other key genes, which rarely, or never, undergo mutations in cancer. We determine whether disrupting these genes in different initial cell states, ranging from normal senescing to pre-transformed cells, leads to abnormal cellular expansion capacity, immortalization, transformation, tumorigenicity or altered complementation by key gene mutations.
In Aim 3, we study whether polycomb complexes (PcG), inclusive of SIRT1, may foster abnormal promoter DNA methylation. PcG, and its signature H3K27me3 mark, are linked to a chromatin state known as """"""""bivalent chromatin"""""""", which holds a group of embryonic/progenitor cell genes in a low, poised, transcription state to maintain stemness and prevent premature lineage commitment. In colon cancer cells, ~ 50% of DNA hypermethylated genes have promoters marked by PcG constituents in embryonic stem/progenitor cells. SIRT1 is included in PRC4, a PcG complex found only in embryonic and mature stem cells, and cancer cells. We now follow our preliminary data to define the nature and function of PcG-SIRT1 complex(es), containing DNMT's and histone methyl-transferases and demethylases, which may convert normal bivalent chromatin such that genes acquire abnormal promoter DNA methylation and silencing.
A common event in tumorigenesis is abnormal, promoter, CpG island, DNA hypermethylation and associated epigenetic gene silencing. We investigate whether this change can foster cancer initiation and the molecular mechanisms though which it arises.
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